Specialized Pro-Resolving Mediators in Asthma

摘要 拟议的实验将测试的假设，专门的亲解决调解人（SPM）和 肺部产生含半胱氨酰的SPM（CysSPM）以反调节促炎反应 并且部分地通过激活嗜酸性粒细胞的促消退亚群来促进肺部炎症的消退。 虽然我们习惯于观察气道炎症和高反应性的增加， 哮喘是由于过度的促炎刺激，哮喘的严重程度和持续时间 恶化也可由内源性抗炎效应物不足引起。半胱氨酰白三烯 在哮喘中发挥促炎作用，但并非所有脂质介质都引发炎症。 现在有几个家庭的专门亲解决调解员（SPM）已被确定， 以急性炎症为特征。这些保护介质是酶促衍生自必需脂肪酸， 酸，并作为激动剂在特定的受体，以促进细胞类型的特异性功能反应，包括 与哮喘相关的嗜酸性粒细胞亚群已经开发了几种药物来阻断CysLT 形成或作用的概念，选择内源性脂质衍生的介质产生促进 哮喘气道反应的解析将颠覆传统思维， 作为天然的前拆分介质和药物设计的新模板。 为了验证我们的假设，我们提出了三个具体目标： 确定急性和慢性过敏性肺部炎症中肺SPM和CysSPM的产生， 建立SPM和CysSPM在解决肺部炎症反应中的作用， 明确肺嗜酸性粒细胞亚群在促进炎症消退中的作用。 本提案的具体目标是揭示解决这些问题的基本机制， 健康和疾病中的过敏性气道反应。

Abstract The proposed experiments will test the hypothesis that specialized pro-resolving mediators (SPMs) and cysteinyl-containing SPMs (CysSPMs) are produced in the lung to counter-regulate pro-phlogistic responses and to promote resolution of lung inflammation, in part via activation of a pro-resolving subset of eosinophils. Although we are accustomed to viewing the increase in airway inflammation and hyper-responsiveness in asthma as the result of an over-abundance of pro-inflammatory stimuli, the severity and duration of an asthma exacerbation could also result from insufficient endogenous anti-inflammatory effectors. Cysteinyl leukotrienes are well appreciated to play pro-phlogistic roles in asthma, but not all lipid mediators initiate inflammation. There are now several families of specialized pro-resolving mediators (SPM) that have been identified and characterized in acute inflammation. These protective mediators are enzymatically derived from essential fatty acids and serve as agonists at specific receptors to transduce cell type specific functional responses, including in eosinophil subsets that are relevant in asthma. With several drugs already developed to block CysLT formation or action, the notion that select endogenous lipid-derived mediators are generated to promote resolution of asthmatic airway responses would turn conventional thinking on its head and identify CysSPMs as natural pro-resolving mediators and novel templates for drug design. To test our hypothesis, we propose three specific aims to:  Determine lung SPM and CysSPM production in acute and chronic allergic lung inflammation,  Establish SPM and CysSPM actions in the resolution of lung inflammatory responses, and  Define roles for lung eosinophil subsets in promoting inflammation resolution. This proposal’s specific aims are directed towards uncovering basic mechanisms that govern the resolution of allergic airway responses in health and disease.